Alzheimer's Disease (AD) is an age-associated dementia for which there is currently no cure. AD is characterized by memory deficits, loss of CNS neurons, and eventually death. Compelling evidence suggests that the prominent neurotoxic event in AD is the presence of the amyloid beta (Ab) peptide, the product of abnormal cleavage of a normal larger protein, and thus that preventing Ab toxicity would be an important therapeutic approach to AD. However, the cellular mechanisms mediating Ab toxicity are still unclear; understanding them should reveal molecular targets for treating AD. The objective of this project is to test one molecular mechanism mediating Ab neurotoxicity, and its behavioral consequences. The central hypothesis of this project is that a key intracellular mechanism mediating Ab neurotoxicity is the aberrant activation of the phosphatase calcineurin (CaN), a signaling element abundant in the CNS that plays a fundamental role in memory function. This project's specific goal is to determine whether the CaN inhibitor FK-506 prevents the detrimental impact of Ab on CNS neurons in vivo. This project will achieve its objective by pursuing the following specific aim: [unreadable] [unreadable] Identify the role of CaN in the onset and progression of cognitive deficits in a transgenic mouse model of Ab-induced neuropathology. The working hypothesis for this aim is that transgenic mice overexpressing mutant human APP will develop significant impairments in associative learning and memory that will be prevented or reversed by pharmacological inhibition of CaN. The results of these studies should identify CaN as a crucial element mediating Ab toxicity. This project will lay the foundation for future studies to develop FK506 as a clinical tool to prevent Ab-associated cognitive deficits. [unreadable] [unreadable] Health relevance: The buildup of the atypical amyloid beta (Ab) protein in the brain is thought to play a key role in the severe behavioral and cognitive impairments that are the most debilitating aspects of Alzheimer's Disease (AD), a terminal age-associated neurodegenerative disease affecting millions of elderly Americans; there is currently no effective treatment for AD. There is general agreement that blocking the neurotoxicity of Ab should decrease the mental impairment typical in AD patients. The goal of this project is to test one pharmacological approach to stop the detrimental effects of Ab on neurons. Specifically, this project will test whether FK506, a drug that inhibits calcineurin (an enzyme that could mediate Ab neurotoxicity), can decrease the adverse effects of Ab in the brains of mice with an AD-like condition. Importantly, since FK506 is already approved for human use as an immunosuppressant, successful results from this project should rapidly lead to clinical trials of this drug for the treatment of AD. [unreadable] [unreadable] [unreadable]